The purpose of this grant was to examine the endogenous mechanisms regulating pain perception, employing as a model system the observation that acute exposure to various severe stressful events induces analgesia. The number and range of qualitatively different stressors include cold-water swims, inescapable foot shock, food deprivation, centrifugal rotation and injections of hypertonic saline, 2-deoxy-D-glucose or insulin. The research to date suggests that multiple pathways may exist that mediate the analgesic effects of these stressors, and moreover, that some of these pathways may be independent of endogenous opiates. Empirical support for these contentions include: a) the analgesia induced by cold-water swims and morphine fail to exhibit cross-tolerance; b) cold-water swims and inescapable foot shock analgesia are not eliminated by the potent opiate antagonist naloxone; c) full and reciprocal cross-tolerance develops between cold-water swim and 2-deoxy-D-glucose analgesia, while the latter displays partial cross-tolerance with morphine; d) hypophysectomy markedly attenuates cold-water swim, inescapable foot shock and insulin analgesia, while potentiating the anti-nociceptive effects of morphine and 2-deoxy-D-glucose; and e) selective periaqueductal gray lesions attenuate the stress-induced analgesic effects.